Project Summary Schizophrenia is a devastating illness with no cure, affecting about 1% of the population worldwide, costing billions of dollars annually. The scientific premise for this proposal is based on accumulating imaging, postmortem, animal model, genetic, and bioinformatics data converging on alterations in the production of bioenergetic molecules in myriad brain regions in this illness. We previously reported abnormally high levels of lactate in living patients with schizophrenia that were strongly associated with poor cognitive function. This finding complements our induced pluripotent stem cell (iPSC) and postmortem work showing higher lactate levels in schizophrenia in iPSC-derived cortical neurons and postmortem anterior cingulate cortex in subjects with schizophrenia. Based on this evidence, we hypothesize that diminished cognitive functioning in schizophrenia is due to impaired bioenergetic metabolism in limbic circuits with increased pathological generation or utilization of lactate in schizophrenia. Specifically, we posit that there is increased production and release of lactate from astrocytes, coupled with increased uptake and utilization of lactate, in lieu of glucose uptake and oxidative phosphorylation, to produce ATP in support of neuronal plasticity in limbic circuits. This new R01 project uses complementary, but distinct approaches, to examine abnormalities of bioenergetic function in schizophrenia. For SA1, we will use magnetic resonance spectroscopy (MRS) to quantify lactate levels and comprehensively characterize patients using neuroimaging, clinical, cognitive, functioning, and metabolic assessments. For Aim 2, cultured human neurons/astrocytes derived from iPSCs obtained in SA1 to assess lactate production and utilization challenges. We will further delineate the functional consequences of lactate production on cellular energy metabolism and neuronal development/function at molecular and cellular levels in cultured human iPSC-derived neurons/astrocytes. In Aim 3, we will use a bioinformatics approach to identify lactate-associated targets for cell-subtype specific studies of biochemical/lactate changes in postmortem brain. Taken together, our aims will comprehensively assess perturbations of lactate and lactate associated pathways across clinical, tissue culture, and postmortem substrates in schizophrenia. By developing a more sophisticated understanding of the pathophysiology of schizophrenia, this project will help identify targets in bioenergetic pathways for development of treatment interventions for this debilitating illness.